Engineering biomimetic environments to study innate immune cell-mediated resistance to therapy in brain metastatic breast cancer

About This Grant

Most deaths from breast cancer occur because the cancer becomes metastatic and spreads to one or more organs. Brain metastatic breast cancer (BMBC) is very aggressive. The prognosis for patients with brain metastases from breast cancer remains poor, often because of resistance to treatment. The environment of BMBC includes tumor cells, immune cells and extracellular matrix (ECM), which is the network of molecules secreted by cells that surround and support them within tissues. Hyaluronic acid (HA) is a primary component of the brain ECM. The immune cells in the BMBC environment are mainly microglia (brain resident immune cells) and macrophages (from blood-derived monocytes). It is not known how these immune cells influence BMBC response to treatment. The goal of this project is to engineer an experimental model incorporating BMBC cells, human microglia, and macrophages as microtumors in HA hydrogels. The model will be used to study how microglia and macrophages influence BMBC cell characteristics and response to treatment. The model may also serve as a platform for the development of new treatment strategies for BMBC or be used for fundamental studies of neurological disorders where disease progression is influenced by immune cells. The project will contribute to training the next generation of the science and engineering workforce by engaging high school students and teachers, as well as undergraduate and graduate students in cancer bioengineering research and enhancing undergraduate and graduate education with new course modules focused on cancer-immune cell interactions. This project aims to develop a biomimetic three-dimensional engineered model incorporating innate immune cells (i.e., macrophages, microglia) to study drug resistance in BMBC. The model will be used to study how microglia/macrophages and their polarization state influence BMBC cell phenotype and therapy response. The research plan is organized under 3 specific aims. Aim 1 will develop and characterize the in vitro bioengineered model by incorporating BMBC cells, human microglia, and human macrophages as spheroids in co-/tri-culture using clinically relevant ratios in a biomimetic HA hydrogel. The engineered innate immune environments will be validated by assessing the expression of BMBC niche markers at the transcriptional and translational level. Aim 2 will elucidate the impact of microglia and macrophages (individually and in combination) as well as their polarization state on BMBC cell phenotype. Aim 3 will determine if the engineered tumor environments support resistance of BMBC cells to therapy, and if therapy resistance can be reversed by targeting the innate immune niche. The educational and outreach plans are integrated with research and include a “Scientist for a Day” program for high school students, a mentored cancer bioengineering interdisciplinary research experience for high school students and teachers (INTEREST) program, providing research opportunities to undergraduate students, and enhancing undergraduate and graduate education by incorporating topics such as cancer-immune cell interactions, and cancer drug resistance into the cancer bioengineering course developed by the principal investigator. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.